Affinity (KD) optimization of monoclonal antibodies is one of the factors that impacts the stoichiometric binding and the corresponding efficacy of a drug. This impacts the dose and the dosing regimen, making the optimum KD a critical component of drug discovery and development. Its importance is further enhanced for bispecific antibodies, where affinity of the drug needs to be optimized with respect to two targets. Mathematical modeling can have critical impact on lead compound optimization. Here we build on previous work of using mathematical models to facilitate lead compound selection, expanding analysis from two membrane bound targets to soluble targets as well. Our analysis reveals the importance of three factors for lead compound optimization: drug affinity to both targets, target turnover rates, and target distribution throughout the body. We describe a method that leverages this information to help make early stage decisions on whether to optimize affinity, and if so, which arm of the bispecific should be optimized. We apply the proposed approach to a variety of scenarios and illustrate the ability to make improved decisions in each case. We integrate results to develop a bispecific antibody KD optimization guide that can be used to improve resource allocation for lead compound selection, accelerating advancement of better compounds. We conclude with a discussion of possible ways to assess the necessary levels of target engagement for affecting disease as part of an integrative approach for model-informed drug discovery and development.